Intrahippocampal dynamics underlying cognitive rigidity

认知僵化背后的海马内动态

• 批准号: 9462227
• 负责人: ELIF ENGIN
• 金额: $ 17.17万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9462227
• 关键词: Address; Affect; Affective; Anxiety; Anxiety Disorders; Applications Grants; Area; Autistic Disorder; Award; Behavior; Behavioral; Behavioral Genetics; Brain; Characteristics; Cognitive; Collection; Communication Research; Complex; Computer Simulation; Data; Detection; Electrophysiology (science); Equilibrium; Ethical Issues; Extinction (Psychology); Failure; Foundations; Freezing; Fright; Future; Genetic; Goals; Grant; Health; Hippocampus (Brain); Histologic; Impairment; In Situ Hybridization; Investigation; Knock-out; Knowledge; Laboratories; Laboratory Research; Lead; Leadership; Learning; Link; Location; Measures; Mediating; Memory; Memory impairment; Mental Depression; Mentored Research Scientist Development Award; Mentors; Modeling; Molecular; Mood Disorders; Mus; Neurobehavioral Manifestations; Occupations; Oral; Outcome; Outcome Study; Output; Pathologic; Pattern; Pharmacology; Phase; Phenotype; Play; Post-Traumatic Stress Disorders; Preparation; Process; Publications; Pyramidal Cells; Research; Research Project Grants; Research Technics; Research Training; Retrieval; Rewards; Rodent; Role; Schizophrenia; Structure; Symptoms; System; Techniques; Testing; Therapeutic; Thinking; Training; Translational Research; Update; Writing; autism spectrum disorder; base; behavioral pharmacology; brain circuitry; career; career development; career networking; cognitive rigidity; conditioned fear; dentate gyrus; entorhinal cortex; experience; flexibility; hippocampal pyramidal neuron; improved; in vivo; knowledge base; memory consolidation; memory retrieval; mouse model; neural model; neuromechanism; neurophysiology; neuropsychiatric disorder; optogenetics; public health relevance; receptor; response; responsible research conduct; skills; therapeutic development

 DESCRIPTION (provided by applicant): This K01 Mentored Research Scientist Development Award aims to provide Dr. Elif Engin with the support required to reach the following career goals: 1) to conduct high-quality, multi-level, multi-technique research to improve our understanding of the brain circuitry and mechanisms of cognitive flexibility / rigidity in health, s well as in neuro-psychiatric disease, 2) to become a leading expert in the area of cognitive flexibility / rigidity; 3) to develop an independent research career, leading a laboratory that doe cutting edge research to address the above questions. The study of complex phenomena such as cognitive flexibility requires a multi-level approach using techniques pertaining to molecular, circuit and behavioral levels of analysis. Dr. Engin has a strong background in molecular and behavioral techniques, having received training in the laboratories of Dr. Dallas Treit, a pioneer in the field of rodent behavioral pharmacology, and Dr. Uwe Rudolph, a world renowned expert in mouse genetics and behavior. Dr. Engin also has experience in histological, pharmacological and optogenetic techniques. The training objectives of the proposed project are to 1) Provide Dr. Engin with training in in vivo electrophysiology in freely moving mice, using cutting-edge multi-tetrode microdrive systems and sophisticated analyses, as well as in other widely-used techniques, such as in situ hybridization, 2) Facilitate Dr. Engin's career development through training in research communication, leadership, grant-writing and other necessary skills to successfully establish and maintain a research laboratory, 3) Establish a knowledge base to address ethical issues in scientific research through training in responsible conduct of research, 4) Extend Dr. Engin's professional network to include possible future collaborators, mentors, mentees, experts in related scientific areas, and 5) Assure the appropriate dissemination of the scientific findings through high quality publications and oral presentations. Dr. Engin's mentoring team is comprised of 3 experts in their respective areas. The primary mentor, Dr. Kerry Ressler, will provide technical training in behavioral tasks related to fear learning and memory, and in sit hybridization, research training in translational research, as well as general training in grant-writing, laboratory management, and the preparation for a job search. Dr. Michael Hasselmo is an expert in hippocampal neurophysiology and computational modeling of neural systems, and will provide training in the analysis of hippocampal spike and field potential data, the theoretica underpinnings of hippocampal encoding and retrieval processes, as well as in career development. Dr. Shantanu Jadhav is an expert in in vivo electrophysiology, especially in the field of hippocampal replay / reactivation, and will provide technical training in the collection ad analysis of electrophysiology data. All three mentors will be involved in responsible conduct of research training. The proposed research project concentrates on the hippocampal correlates of cognitive rigidity. Despite being a cognitive symptom in a large number of neuro-psychiatric diseases, which together affect more than 30 million people in the US, a systematic study of the neural mechanisms of cognitive rigidity has not been undertaken. The overall research objective of this application is to determine the hippocampal circuit level dynamics underlying cognitive rigidity by utilizing a mouse model developed by Drs. Engin and Rudolph, which has a specific cognitive rigidity phenotype. The central hypothesis is that the cognitive rigidity phenotype is associated with a deficiency in reconsolidation, specifically in the memory destabilization phase. In our first specific aim, we propose to record local field potentials, spike activity and place cel activity in freely moving mice learning to associate rewards with specific locations on a maze using multi-tetrode micro drives to 1) Determine whether cognitive rigidity is associated with deficiencies in the hippocampal novelty response, as measured by the suppression of the hippocampal theta activity, 2) Establish if cognitively rigid mice show retrieval bias in the retrieval/encoding balance, as measured by the preferred spiking phase of the CA1 pyramidal neurons within the theta cycle, and 3) Determine whether rigid behavior is reflected in rigid hippocampal replay of old trajectories, as measured by the persistence of the replay of old reward trajectories following a reversal of the reward-location contingency. Our hypothesis is that the α5DGKO mice will have a dampened hippocampal novelty response and a bias towards retrieval, which would impair memory destabilization upon reactivation, and that this deficiency would be reflected in rigid hippocampal replay of old trajectories. In our second specific aim, we propose to use a combined pharmacological-genetic-behavioral approach to determine whether memory destabilization during reconsolidation is impaired in cognitively rigid mice. We believe the outcomes of the proposed studies will have a positive impact because the hippocampus-mediated processes constitute the foundation for the systematic study of the brain mechanisms of cognitive flexibility and the development of therapeutic strategies for neuro-psychiatric disorders. The knowledge, experience and data gained from this proposal will lead directly to the study of hippocampal outputs to downstream structures and the larger brain network mediating adaptive cognitive flexibility, which will be proposed in an R01 grant application in 3-4 years of the award.

 描述（由适用提供）：该K01指导的研究科学家发展奖旨在向Elif Engin博士提供实现以下职业目标所需的支持：1）进行高质量，多层次，多技术研究，以提高我们对脑电路的理解，并在健康方面的认知灵活性 /固执方面的智力柔性 /稳定性，并在健康方面具有良好的态度。刚性； 3）发展独立的研究职业，领导了一项实验室进行尖端研究以解决上述问题的实验室。对复杂现象（例如认知灵活性）的研究需要使用与分子，电路和行为分析水平有关的技术进行多层次方法。 Engin博士在分子和行为技术方面具有强大的背景，并接受了啮齿动物行为药理学领域的先驱达拉斯·特雷特（Dallas Treit）的实验室的培训，以及乌韦·鲁道夫（Uwe Rudolph）博士，他是小鼠遗传学和行为方面享有的世界专家。 Engin博士还具有组织学，药理和光遗传学技术的经验。 The training objectives of the proposed project are to 1) Provide Dr. Engin with training in vivo electrophysiology in free moving mice, using cutting-edge multi-tetrode microdrive systems and sophisticated analyses, as well as in other wide-used techniques, such as in situ hybridization, 2) Facilitate Dr. Engin's career development through training in research communication, leadership, grant-writing and other necessary skills to successfully establish and maintain a research laboratory, 3)建立一个知识基础，通过负责任的研究进行培训，以解决科学研究中的道德问题，4）扩展Engin博士的专业网络，包括未来的合作者，导师，Menetes，相关科学领域的专家以及5）通过高质量的出版物和口头表现适当地传播科学发现。 Engin博士的修订 团队在各自领域完成了3名专家。主要导师克里·雷斯勒（Kerry Ressler）博士将提供与恐惧学习和记忆有关的行为任务的技术培训，以及在现场杂交，转化研究中的研究培训，以及赠款写作的一般培训，实验室管理和求职准备。 Michael Hasselmo博士是神经元系统海马神经生理学和计算建模的专家，并将在分析海马尖峰和现场潜在数据的分析中提供培训，这是海马编码和检索过程的基础定理的基础。 Shantanu Jadhav博士是体内电生理学专家，尤其是在海马重播 /重新激活领域，并将在电生理数据的收集AD分析中提供技术培训。这三位导师将参与负责任的研究培训。拟议的研究项目集中于认知僵化的海马相关性。尽管在许多神经精神疾病中是一种认知症状，这些疾病在美国产生了超过3000万人的影响，但尚未进行对认知僵化神经机制的系统研究。该应用程序的总体研究目标是通过使用DRS开发的小鼠模型来确定认知刚度的海马电路水平动力学。 Engin和Rudolph，具有特定的认知僵化表型。中心假设是认知僵化表型与重新溶解的缺陷有关，特别是在记忆不稳定阶段。在我们的第一个特定目标中，我们建议记录当地的现场潜力，尖峰活动并将CEL活性放在自由移动的小鼠学习中，以将奖励与迷宫上的特定位置联系起来，使用多四极微驱动器与1）确定认知刚度是否与海马新颖性反应中的缺乏有关在检索/编码平衡中，通过在Theta周期内CA1锥体神经元的首选尖峰阶段进行衡量，3）确定是否在旧轨迹的刚性海马重放中反映了刚性行为，这是通过在奖励定位重新分配率的旧奖励轨迹的持久性来衡量的。我们的假设是，α5DGKO小鼠将具有衰减的海马新颖性反应和对检索的偏见，这会在重新激活时会损害记忆力不稳定，并且这种缺乏将反映在刚性海马的旧轨迹中。在我们的第二个特定目标中，我们建议使用合并的药物遗传行为方法来确定在认知上刚性小鼠中是否会损害重新溶解过程中的记忆不稳定。我们认为，拟议研究的结果将产生积极的影响，因为海马介导的过程构成了对认知灵活性的大脑机制的系统研究和神经精神疾病理论的发展。从该提案中获得的知识，经验和数据将直接导致对下游结构的海马产量和较大的大脑网络进行介导适应性认知灵活性的较大的大脑网络，这将在3-4的R01赠款应用中提出。 奖励年。